Alkylation of crosslinked polymers containing N or amino or ammonium groups

ABSTRACT

The invention relates to a method for alkylating cross-linked polymers containing N- or amino, ammonium or spiro-bicyclic ammonium groups. According to said method, the gelated polymers, obtained by polymerization and cross-linking, are a) optionally, deprotonated in water, an organic solvent or in a mixture of an organic solvent and water, by adding a base, b) optionally, washed once or more with water, an organic solvent or a mixture of an organic solvent and water, then c) one or more alkylators are added to the gel suspension which is stirred in water, an organic solvent or in a mixture of an organic solvent and water, at a temperature of between 5 and 160° C. at normal or increased pressure, with a base being added after a short mixing time and d) reprotonation is carried out using a mineral acid, optionally after one or more washing steps, resulting in the alkylated, cross-linked polymers containing N- or amino, ammonium or spirobicyclic ammonium groups, accordingly.

The invention relates to a process for the efficient alkylation ofpolymers containing N or amino or ammonium groups, which are employed,for example, in medicine to lower the cholesterol level by means ofbinding of the bile acids or of bile acid salts.

The term alkylation is very comprehensive and as a definition includesthe addition of an alkyl group to a molecule. Alkylation reactions playa crucial role in the chemical industry—in particular they have anespecially important role in pharmaceutical chemistry, since, on the onehand, because of the often very high product price the efficiency of thereaction must be guaranteed and, on the other hand, the by-productsformed in the reaction must be kept as low as possible because of theexpensive purification steps.

The alkylation of gels and polymers is of special importance, since herenot only the reaction kinetics described in the literature, such as forhomogeneous solutions, apply but the alkylation is also subject todiffusion-controlled conditions to an increased extent.

In the processes hitherto disclosed in the prior art (e.g.: WO 98/43653;WO 99/33452; EP 0 909 768; WO 99/34786; WO 98/29107; WO 00/32656 etc.)for the alkylation of crosslinked polymers containing N or amino,ammonium or spirobicyclic ammonium groups, such as, for example, in thealkylation, for example, of polyallylamine hydrochloride crosslinkedwith epichlorohydrin, during the reaction considerable amounts ofhalogen-containing by-products are formed, such as, say, for example,chlorodecane and/or chloroquat, and in the use of methanol as a solventin combination with aqueous sodium hydroxide solution in four equivalentportions by-products such as methoxydecane and/or methoxyquat etc. areformed. A further disadvantage of hitherto customary alkylationprocesses are the unsatisfactory alkylation yields and very longreaction times. Moreover, the considerable proportion of volatileorganic impurities must be eliminated from the polymers or gelssubsequently by a number of alcohol/NaCl washes or alcohol washes.

An object of the present invention was accordingly to find an alkylationmethod for crosslinked gels or polymers containing N or amino, ammoniumor spirobicyclic ammonium groups which guarantees short reaction times,high alkylation yields and a formation of by-products which is as low aspossible.

Unexpectedly, it was possible to achieve this object by means of analkylation method which includes not only the optimum alkylationconditions during the reaction, but also the preparation of the gel tobe alkylated.

The invention therefore relates to a process for the alkylation ofcrosslinked polymers containing N or amino, ammonium or spirobicyclicammonium groups, which is characterized in that it comprises optionallydeprotonating the gelled polymers obtained by polymerization andcrosslinking

-   -   a) in water, an organic solvent or in an organic solvent/water        mixture by addition of a base,    -   b) optionally washing the polymers 1 or more times with water,        an organic solvent or an organic solvent/water mixture, then    -   c) adding one or more alkylators at atmospheric or elevated        pressure at a temperature of between 5 and 160° C. to the gel        suspension stirred in water, an organic solvent or in an organic        solvent/water mixture, and, after a mixing time of 1 to 60        minutes adding a base continually or in plural portions in such        a way that the pH is between 8 and 13.5, and    -   d) subsequently carrying out the reprotonation by means of a        mineral acid, if appropriate after one or more washing steps,        whereby the correspondingly alkylated, crosslinked polymers        containing N or amino, ammonium or spirobicyclic ammonium groups        are obtained. In the process according to the invention,        crosslinked polymers containing N or amino, ammonium or        spirobicyclic ammonium groups are alkylated.

These polymers are polymers which are described, for example, in WO00/32656, WO 00/38664, WO 99/33452, WO 99/22721, WO 98/43653, U.S. Pat.No. 5,624,963 and U.S. Pat. No. 5,496,545.

Suitable polymers for the alkylation process according to the inventionare, in particular, cationic polymers. The cationic polymers include,inter alia, those polymers which contain an amine N atom, such as, forexample, primary, secondary or tertiary amine groups or salts thereof,quaternary ammonium groups and/or spirobicyclic ammonium groups.Additional cationic groups include amidino, guanidino, imino etc. Thecationic polymer is distinguished in that it has a positive charge atphysiological pH.

Examples of suitable cationic polymers include polyvinylamines,polyallylamines, polydiallylamines, polyvinylimidazoles,polydiallylalkylamines, polyethylenimines etc., and also polymerscomprising the repeating units disclosed in, for example, WO 00/32656,page 7f.; WO 98/43653, page 4f.; U.S. Pat. No. 5,496,545, column 2 to 4;U.S. Pat. No. 5,624,963; WO 98/29107 etc.

The polymers employed are additionally crosslinked. The crosslinking canin this case be carried out even during the polymerization or else alsoonly following the polymerization. Suitable crosslinking agents includethe crosslinking agents known from the references already cited.Examples of these are epichlorohydrin, succinyl dichloride,ethylenediamine, toluene diisocyanates, diacrylates, dimethacrylates,methylenebisacrylamides, dichloroethane, dichloropropane, etc.

The polymers employed for the process according to the inventionadditionally have negatively charged counterions. These counterions canbe organic or inorganic ions or combinations thereof. Suitablecounterions likewise include the counterions disclosed in the prior artalready cited. Examples of suitable inorganic ions are halides, inparticular chloride, phosphates, phosphites, carbonates, bicarbonates,sulfates, bisulfates, hydroxides, nitrates, persulfates, sulfites andsulfides. Examples of suitable organic ions are acetates, ascorbates,benzoates, lactates, fumarates, maleates, pyruvates, citrates,dihydrogencitrates, hydrogencitrates, propionates, butyrates, oxalates,succinates, tartrates, cholates etc.

The polymers are prepared as in the prior art, for example as describedin WO 99/33452, WO 99/22721, WO 98/43653, U.S. Pat. No. 5,624,963 andU.S. Pat. No. 5,496,545.

Following the polymerization, crosslinking and gelling time, thealkylation according to the invention of the polymer contained in gelform is then carried out. The gel to be alkylated is optionallyadditionally comminuted or cut before hand.

Also before the alkylation reaction, the optionally cut crude gel iswashed with a water/base mixture, an organic solvent/base mixture or amixture of organic solvents, water and base so that the gel is presentin completely or partially deprotonated form. If appropriate, thedeprotonation can be dispensed with and the optionally cut crude gel isthen washed only with water, an organic solvent or a mixture of organicsolvent and water. Preferably, however, the polymer is deprotonated.

Step a) is carried out here at a temperature of 1° C. to 100° C.,preferably at 5 to 90° C., particularly preferably at 10 to 40° C.,using water, preferably using completely deionized water, or a solventor a mixture, and a base suitable for the deprotonation. Suitablesolvents are C₁–C₁₀alcohols, formamide, dimethylformamide (DMF),tetrahydrofuran (THF), acetonitrile, dimethyl sulfoxide (DMSO) andhexamethylphosphoramide (HMPA). However, mixtures thereof or mixtureswith water can also be employed. Preferably, however, a C₁–C₁₀alcohol isused.

The alcohols can in this case be linear or branched, such as, forexample, methanol, ethanol, i-propanol, butanol.

Particularly preferably, C₁–C₆alcohol, in particular methanol, ethanoland i-propanol, are employed as solvents.

Suitable bases are hydroxides, such as, for example, NaOH, KOH, LiOH,Ca(OH)₂, NH₄OH, carbonates, such as, for example, Na₂CO₃, K₂CO₃ etc.NaOH, KOH or NH₄OH is preferably used.

The amount of base to be used differs greatly between the respectivegels, and depends on the amount of counterions.

Per mol of counterions, 0.1 to 5 mol of base, preferably 0.5 to 3 moland particularly preferably 0.7 to 2 mol of base, are added here. Ifdesired, greater excesses of base can also be employed.

By further washing of the deprotonated gel (step b) with an organicsolvent, a solvent mixture or water/organic solvent mixtures at atemperature from 1 to 100° C., the content of salts in the gel can begreatly reduced. Preferably, for further washing the solvent employed instep a) is used. Step b) can optionally be dispensed with, otherwise thedeprotonated gel is washed 1 to 8 times. Preferably, the gel is washedone to three times. If appropriate, steps a) and b) can be dispensedwith completely.

The alkylators are then added to the gel suspension stirred in water orsolvent or solvent mixture. (Step c)

Alkylators are understood as meaning reactants which, when they arereacted with a crosslinked polymer, cause an alkyl group or a derivativethereof, such as, for example, a substituted alkyl group etc., to bindcovalently to one or more of the N atoms in the polymer.

Suitable alkylators in this case are compounds of the formula RX, whichcontain an alkyl group or an alkyl derivative having 1 to 24 C atoms(R), which is bonded to a leaving group (X), such as are already knownfrom the prior art already cited.

R is accordingly a linear, branched or cyclic alkyl radical having 1 to24 C atoms, preferably having 4 to 20 C atoms, or an alkyl derivative,such as, for example, a C₁–C₂₀—, preferably C₄–C₂₀-hydroxyalkyl group,C₇–C₂₀-aralkyl group, C₁–C₂₀-, preferably C₄–C₂₀-alkylammonium group orC₁–C₂₀-, preferably C₄–C₂₀-alkylamido group.

X is an electrophilic leaving group, for example from the groupconsisting of the halides, such as, for example, chloride, bromide,fluoride, iodide, or, for example, a leaving group such as epoxy,tosylate, mesylate or triflate. The alkylator can in this case containone or more leaving groups.

Examples of preferred alkylators are C₁–C₂₄-alkyl halides, such as, forexample, n-butyl halide, n-hexyl halide, n-decyl halide, n-dodecylhalide, n-tetradecyl halide, n-octadecyl halide, etc.,C₁–C₂₄-dihaloalkanes, such as, for example, 1,10-dihalodecane, etc.,C₁–C₂₄-hydroxyalkyl halides, such as, for example, 11-halo-1-undecanol,etc., C₁–C₂₄-aralkyl halides, such as, for example, benzyl halide,substituted benzyl halides, etc., C₁–C₂₄-alkylepoxyammonium salts, suchas, for example, glycidylpropyltrimethylammonium salts, etc.,C₁–C₂₄-epoxyalkylamides, such as, for example,N-(2,3-epoxypropane)butyramide, N-(2,3-epoxypropane)hexanamide, etc.,C₁–C₂₄-alkyl halide ammonium salts, such as, for example,(4-halobutyl)trimethylammonium salt, (6-halohexyl)trimethylammoniumsalt, (8-halooctyl)trimethylammonium salt,(10-halodecyl)trimethylammonium salt, (12-halododecyl)trimethylammoniumsalt, etc.

Preferred alkylators are bromodecane and 6-bromohexyltrimethylammoniumbromide.

In the alkylation reaction, one or more alkylators can in this case beadded.

The alkylators are employed in the process according to the inventiondepending on the desired degree of alkylation. The synthesis ofcolesevelam hydrochloride should, for example, yield a polymer structurein which approximately 12% of the amines of the polyallylamine structureare crosslinked, approximately 40% of the amines of the polyallylaminestructure are provided with decyl groups and approximately 34% of theamines of the polyallylamine structure are provided withtrimethylammoniumhexyl groups, and also approximately 14% of the aminesof the polyallylamine structure remain as primary amines (PolymerPreprints 2000, 41(1), 735–736). The determination of the differentdegrees of alkylation can be determined very simply in comparison with aselected reference substance by analysis of the C/N ratio and the numberof free amines (titratable amines). Thus, for example, for the synthesisof colesevelam hydrochloride according to the prior art, for instance,0.16 (±4%) mol of monoquat and 0.15 (±4%) mol of bromodecane areemployed for a standard batch of 187.5 g of moist crude gel; in theprocess according to the invention, for example the amount of thealkylators can be reduced at most to 0.1536 mol of monoquat and 0.1326mol of bromodecane, which corresponds to a reduction by 15% ofbromodecane and 8% of monoquat. The asymmetric modification of thealkylators lies in the fact that each alkylator is subject to differentalkylation yields.

The addition of the alkylators is carried out at a temperature between 5and 160° C. and may take place not only at atmospheric pressure but alsoat elevated pressure. When elevated pressure is employed, the gaugepressure is adjusted to 0.1–20 bar, preferably 0.1–5 bar and morepreferably 0.1–2 bar.

Before or after the addition, for example, the gel suspended in thesolvent can be heated to 25 to 160° C., preferably to 35 to 120° C. andparticularly preferably to boiling temperature of the respectivesolvent, depending on the solvent.

After addition of the alkylator(s), the reaction mixture is additionallythoroughly mixed, the mixing time being between 1 and 60 minutes,preferably 5 to 50 minutes and particularly preferably 10 to 40 minutes.If desired, longer mixing times can also be kept to, but afford noadditional advantage.

The continuous or quasi-continuous addition of base is then begun.

A suitable base for this, depending on the solvent used, is NaOH, KOH,NH₄OH, LiOH, Ca(OH)₂, Ba(OH)₂, NaH and NaNH₂. NaOH is preferablyemployed.

The base is best added such that the pH remains constant during theentire reaction time. Depending on the pH electrode and calibration ofthe electrode, the values may differ—therefore an optimum pH range of 8to 13.5, preferably 10.5 to 11.5, is specified. Once the optimum amountof base has been determined according to the kinetics, it is thenpossible, according to calculation by means of the exponentialequalization function, also to carry out the addition of basequasi-continuously in a number of portions (at least 6, preferably atleast 16, particularly preferably more than 16, portions), but atdifferent time intervals. Corresponding to the equalization function, acontinuous addition of base can also be carried out polygonally.

Too high a pH or base content leads, on the one hand, to the increasedformation of alkoxy impurities, such as, for example, methoxydecane,ethoxydecane, (6-methoxyhexyl)trimethylammonium bromide, etc., in thecase of the use of an alcohol as a solvent; too low a pH or base contentdecreases the reaction rate and increases the formation of, for example,Cl-alkane impurities.

Thus in the alkylation, for example, of crosslinked polymers whichcontain hydrochloride ions, such as, for example, polydiallylaminehydrochloride or polyallylamine hydrochloride, using an alkylator whereX=bromide only a continuous addition of, for example, NaOH correspondingto the kinetics or corresponding to the formation of hydrobromic acidleads to no hydrochloric acid being formed by the amine hydrochlorideions still present or the NaCl salt remaining in the gel, which thenreacts with the alkylators to give undesired Cl-alkane compounds.Cl-alkane compounds and alkoxyalkane compounds must be eliminated fromthe gel after reaction has taken place by washing a number of times, forexample, with alcohol or alcohol/NaCl solutions.

According to the invention, in comparison with the prior art, one ormore washing steps can be dispensed with because of the contaminationprofile, which is lower by up to 70%.

The alkylation reaction is complete when at least 95 to 99% of thealkylators have reacted, which according to the invention takes place 30to 50% more rapidly in comparison with the prior art.

After the end of the reaction, in step d) the gel is reprotonated inwater, an organic solvent or in an organic solvent/water mixture byaddition of an acid.

Suitable organic solvents are in this case linear, branched or cyclicC₁–C₁₀-alcohols having 1 to 3 OH groups, such as, for example, methanol,ethanol, isopropanol, n-propanol, n-butanol, sec-butanol, hexanol,ethylhexanol, cyclopentanol, cyclohexanol, cyclooctanol,cyclohexanediol, glycol, glycerol etc., and also ketones, such as, forexample, acetone, methyl ethyl ketone, methyl isopropyl ketone, methylisobutyl ketone, diisopropyl ketone, cyclohexanone etc., nitriles, suchas, for example, acetonitrile etc. and ethers, such as, for example,tetrahydrofuran, methyl tert-butyl ether, dimethoxyethane, etc.

C₁–C₄-alkohols are preferred and methanol is particularly preferablyemployed. Organic solvents here are also understood as meaning mixturesof the solvents mentioned above.

Suitable acids for the reprotonation are all mineral acids and organicacids which lead to the counterions already mentioned.

These are, for example, HCl, HBr, H₂SO₄, H₃PO₄, HNO₃ etc. and formicacid, acetic acid, oxalic acid, citric acid, pyruvic acid, maleic acid,fumaric acid, propionic acid, tartaric acid etc.

The gel is in this case firstly stirred in water, the organic solvent,the mixture of various organic solvents or the solvent/water mixture.The stirring time is in this case a few minutes to a number of hours,preferably 1 to 60 minutes, particularly preferably for 5 to 30 minutes.If desired, longer stirring times are also possible. The temperature isbetween 1 and 100° C., preferably between 5 to 90° C. and particularlypreferably between 10 to 40° C.

The mixture is then treated with that amount of acid which leads to thecomplete or partial reprotonation of the amines in the polymer.

If desired, the reprotonation of the alkylated gel, however, can also becarried out at the end of one or more alcohol and/or alcohol/salt, forexample NaCl, washes and/or water and/or water/salt, such as, forexample NaCl, washes.

In the case of the use of alkylators which carry quaternary ammoniumgroups, such as, for example, (6-bromohexyl)trimethylammonium bromide,in comparison with the prior art a large part of the correspondingbromide ions can be performed by chloride ions by washing less oftenwith water/NaCl, since the total amount of various salts is lower due toelimination of hydrochloride ions before the start of the alkylationreaction.

Following the reprotonation and in the case of bromide/chlorideexchange, excess NaCl can be eliminated in the gel by repeated washingwith water. The moist gel is dried according to the prior art.

By means of the process according to the invention it is possible toalkylate crosslinked gels or polymers containing N or amino, ammonium orspirobicyclic ammonium groups in an extremely efficient manner, shortreaction times, high alkylation yields and a formation of by-productswhich is as low as possible being guaranteed.

Preferably, the process according to the invention for the alkylation ofcrosslinked polyallylamine and polydiallylamine hydrochlorides havingfunctional groups containing N or amino, ammonium or spirobicyclicammonium groups is employed.

The advantages of the process according to the invention in this case inparticular lie in the significantly lower formation of impurities, suchas chlorodecane, methoxydecane, chloroqat and methoxyquat, and in themarkedly reduced amount (up to 15% less consumption) of the amount ofalkylator needing to be employed. Moreover, a result of the lowerformation of impurities, fewer washing steps are as necessary incomparison with the prior art.

A further advantage is the higher throughput due to reduction of thereaction time by about 30–50% (from about 20 h, or 26 h according to theprior art, to 10–13 h).

EXAMPLE 1 Preparation of a Polyallylamine Hydrochloride Crosslinked WithEpichlorohydrin, Alkylation and Washing:

Crosslinking:

1500 g (8.02 mol) of an aqueous 50% strength polyallylaminehydrochloride solution were introduced into a 4.5 I Schmizo and dilutedwith 2037 g of completely deionized water with stirring and nitrogenflushing. The mixture was then adjusted to a pH of between 10.0–10.4 at10° C. using 393 g (4.92 mol) of sodium hydroxide solution (50%strength). The solution obtained was stirred for 60 minutes and in thecourse of this cooled to an internal temperature of 5° C. The reactionmixture was treated with 44.53 g (0.48 mol) of epichlorohydrin, stirredat 5° C. for 30 minutes and then drained into in a plastic vessel togel. The yield was 100% of theory. After a gelling time of 24 hours, thegel was forced twice through a sieve having a mesh width of 1.5 mm.

Deprotonation and Washing of the Cut Crude Gel (Steps a and b):

187.5 g of cut gel (parallelepipeds having an edge length of about 2×2×2mm) were introduced into a glass sinter funnel (glass frit G2; 14 cm Ø),treated with 337.5 g of methanol and 15 g of NaOH (50% strength),suspended with stirring for 20 minutes and then, after allowing tosettle (about 15 min), the liquid was filtered off to the surface. Thegel cake was then additionally treated 3 times with 310 g of methanoleach time, stirred for 20 minutes and in each case the liquid wasfiltered off to the surface with suction.

Alkylation (Step c):

The methanol-moist crude gel (375 g) was introduced into a 500 mlSchmizo, made up to a total volume of 600 ml under a nitrogen atmosphereusing about 125 g of methanol and the mixture was heated to 50° C. 46.9g (0.155 mol) of (6-bromohexyl)trimethylammonium bromide in 25 g ofmethanol and 31.0 g (0.14 mol) of 1-bromodecane were then added to theheated gel suspension with stirring. After addition of the alkylatorshad taken place, the reaction solution was stirred under reflux for 8hours.

From the time when refluxing commenced, corresponding to the tablebelow, 23 g of sodium hydroxide solution (50% strength) were addedeither discontinuously after different time intervals but in equalportions (A), or continuously at equal time intervals but in differentportions (B), or continuously after different time intervals but inequal portions (C).

Discontinuous (A) Continuous (B) Continuous(C) Time NaOH Time NaOH TimeNaOH intervals for 50% interval 50% interval 50% next NaOH strength forNaOH strength for NaOH strength addition [g] addition [g] addition [g] 0 min 1.44 30 min 4.17 13 min 1.44 14 min 1.44 30 min 3.45 13 min 1.4414 min 1.44 30 min 2.86 13 min 1.44 14 min 1.44 30 min 2.36 13 min 1.4414 min 1.44 30 min 1.96 14 min 1.44 14 min 1.44 30 min 1.62 16 min 1.4416 min 1.44 30 min 1.34 18 min 1.44 18 min 1.44 30 min 1.11 20 min 1.4420 min 1.44 30 min 0.92 25 min 1.44 25 min 1.44 30 min 0.76 27 min 1.4427 min 1.44 30 min 0.63 29 min 1.44 29 min 1.44 30 min 0.52 34 min 1.4434 min 1.44 30 min 0.43 45 min 1.44 45 min 1.44 30 min 0.36 60 min 1.4465 min 1.44 30 min 0.30 70 min 1.44 90 min 1.44 30 min 0.24 70 min 1.44

After addition of the sodium hydroxide solution had taken place, thestirrer was switched off and the gel suspension was additionallyrefluxed for a further 2 hours.

Reprotonation (Step d)

The mixture was then cooled to 20° C. and the gel suspension was treatedwith 34.2 g of concentrated hydrochloric acid (36% strength) withstirring (20 minutes).

Washing of the Alkylated Gel:

The gel suspension obtained was in each case treated 4 times withstirring with 225 g of methanol and 34.2 g of 2 molar NaCl solution and,after a stirring time of 20 minutes, the liquid was filtered off to thesurface. The gel cake was then washed 6 times with 525 g of 2 molar NaClsolution each time and 6 times with 490 ml of deionized water each time.

The gel cake obtained was dried at 60° C. and a vacuum of 20 mbar to adrying loss of at most 3%. 75.4 g of product having a dry substancecontent of 1.4% were obtained.

In comparison with the prior art, after the end of the alkylationreaction the content of organic impurities in the reaction solution canbe decreased:

Chlorodecane Methoxydecane Chloroquat Methoxyquat Prior art   3–4 g/l1.8–2.2 g/l   5–6 g/l 5–7 g/l According 0.5–0.8 g/l 0.9–1.4 g/l 1.8–2.8g/l 5–7 g/l to the invention

In comparison with the prior art, the content of chlorodecane in themoist gel after the fourth methanol/NaCl wash is only more 600 to 800ppm instead of 2500 to 3000 ppm.

A comparison example for the alkylation is found according to the priorart in the reference polymer preprints 2000, 41(1), pages 735–736.

1. A process for the alkylation of crosslinked polymers containing anamine N atom which comprises: a) deprotonating a gelled polymer obtainedby polymerization and crosslinking in water, an organic solvent or in anorganic solvent/water mixture by addition of a base, b) optionallywashing the gelled polymer one or more times with water, an organicsolvent or an organic solvent/water mixture, then c) adding one or morealkylators at atmospheric or elevated pressure at a temperature ofbetween 5 and 160° C. to a gel suspension formed by stirring said gelpolymer in water, an organic solvent or in an organic solvent/watermixture, and, after a mixing time of 1 to 60 minutes, adding the basecontinually or in plural portions in such a way that the pH is between 8and 13.5, and d) reprotonating by means of a mineral acid, after one ormore optional washing steps, whereby the correspondingly alkylated,crosslinked polymers containing an amine N atom is obtained.
 2. Theprocess as claimed in claim 1, wherein the polymers containing an amineN atom are crosslinked, cationic polymers which contain primary,secondary or tertiary amine groups or salts thereof and/or quatemaryammonium groups and/or spirobicyclic ammonium groups, amidino groups,guanidino groups or imino groups, and also negatively charged inorganicand/or organic counterions selected from the group consisting ofhalides, phosphates, phosphites, carbonates, bicarbonates, sulfates,bisulfates, hydroxides, nitrates, persulfates, sulfites and sulfides,acetates, ascorbates, benzoates, lactates, fumarates, maleates,pyruvates, citrates, dihydrogencitrates, hydrogen citrates,propinonates, butyrates, oxalates, succinates, tartrates and cholates.3. The process as claimed in claim 1, wherein the polymers containing anamine N atom are crosslinked polyvinylamines, polyallylamines,polydiallylamines, polyvinylimidazoles, polydiallylalkylamines orpolyethylenimines having suitable counterions.
 4. The process as claimedin claim 1, wherein said gel employed in step a) optionally iscomminuted or cut and treated at a temperature of 1 to 100° C. withwater, an organic solvent from the group consisting of C₁–C₁₀-alcohol,formamide, dimethylformamide, tetrahydrofuran, acetonitrile, dimethylsulfoxide and hexamethylphosphoramide or with a mixture thereof or witha mixture with water and a base suitable for deprotonation from thegroup consisting of NaOH, KOH, LiOH, Ca(OH)_(2,) NH₄OH, Na₂CO₃ andK₂CO_(3,) wherein 0.1 to 5 mol of base are added per mol of counterion.5. The process as claimed in claim 1, wherein in step b) the gelledpolymer is washed 1 to 3 times at a temperature of 1 to 100° C. withwater or with an organic solvent selected from the group consisting ofC₁–C₁₀-alcohol, formamide, dimethylformamide, tetrahydrofuran,acetonitrile, dimethyl sulfoxide and hexamethylphosphoramide or with amixture thereof or with a mixture with water.
 6. The process as claimedin claim 1, wherein in step c) one or more alkylators of the formula RXare added at a temperature between 5 and 1600C to the gelled polymerstirred in water, in an organic solvent from the group consisting ofC₁–C₁₀-alcohol, formamide, dimethylformamide, tetrahydrofuran,acetonitrile, dimethy 1 sulfoxide and hexamethylphosphoramide or in amixture thereof or in a mixture with water, wherein the formula RX R isa linear, branched or cyclic alkyl radical having 1 to 24 C atoms, aC₁–C₂₀-hydroxyalkyl group, a C₇–C₂₀-aralkyl group, aC₁–C₂₀-alkylammonium group or a C₁–C₂₀-aklylamido group and X is anelectrophilic leaving group from the group consisting of fluoride,chloride, bromide, iodide, epoxy, tosylate, mesylate or triflate, thealkylator optionally containing one or more leaving groups.
 7. Theprocess as claimed in claim 6, wherein the suspended gel is heated to 35to 120° C. before or after the addition of the alkylator.
 8. The processas claimed in claim 1, wherein in step c) the base employed is NaOH,KOH, NH₄OH, LiOH, Ca(OH)₂, Ba(OH)₂, NaH and NaNH₂.
 9. The process asclaimed in claim 1, wherein in step d) the gel suspension from step c)is firstly stirred at 1 to 100° C. for a few minutes to a number ofhours in water, the organic solvent or the solvent/water mixture, and isthen treated with that amount of mineral acids or organic acids whichleads to the counterions originally present in the polymer and topartial to complete reprotonation.
 10. The process as claimed in claim1, wherein the reprotonation in step d) is carried out after one or morealcohol and/or alcohol/salt washes and/or water and/or water/saltwashes.
 11. The process according to claim 1 wherein said amine N atomis present as an amino, ammonium or spirobicyclic ammonium group.